Evidence map›Paper›PMID 36934521›Full record

ArticleEuropean journal of medicinal chemistry2023

Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity.

Benjamin N Atkinson, Nicky J Willis, Yuguang Zhao, Chandni Patel, Sarah Frew, Kathryn Costelloe, Lorenza Magno, Fredrik Svensson, E Yvonne Jones, Paul V Fish

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in European journal of medicinal chemistry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
1.5field-weighted citation impact, top 18% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed, 10 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 2 institutions in 1 country.

Benjamin N AtkinsonAlzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, London, WC1E 6BT, UK.
Nicky J WillisAlzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, London, WC1E 6BT, UK.
Yuguang ZhaoDivision of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Oxford, OX3 7BN, UK.
Chandni PatelAlzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, London, WC1E 6BT, UK.
Sarah FrewAlzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, London, WC1E 6BT, UK.
Kathryn CostelloeAlzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, London, WC1E 6BT, UK.
Lorenza MagnoAlzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, London, WC1E 6BT, UK.
Fredrik SvenssonAlzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, London, WC1E 6BT, UK. Electronic address: f.svensson@ucl.ac.uk.
E Yvonne JonesDivision of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Oxford, OX3 7BN, UK.
Paul V FishAlzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, London, WC1E 6BT, UK.
Alzheimer’s Research UK · GBCentre for Human Genetics · GB

Funding

Medical Research Council MR/T000503/1
6 · The paper itself

Abstract

N-Acyl indolines 4 are potent, non-covalent Notum inhibitors developed from a covalent virtual screening hit 2a. The lead compounds were simple to synthesise, achieved excellent potency in a biochemical Notum-OPTS assay and restored Wnt signalling in a cell-based TCF/LEF reporter assay. Multiple high resolution X-ray structures established a common binding mode of these inhibitors with the indoline bound centred in the palmiteolate pocket with key interactions being aromatic stacking and a water mediated hydrogen bond to the oxyanion hole. These N-acyl indolines 4 will be useful tools for use in vitro studies to investigate the role of Notum in disease models, especially when paired with a structurally related covalent inhibitor (e.g. 4w and 2a). Overall, this study highlights the designed switch from covalent to non-covalent Notum inhibitors and so illustrates a complementary approach for hit generation and target inhibition.

Indexed as

Carboxylic Ester HydrolasesWnt Signaling PathwayBiophysical PhenomenaCarboxylic Ester HydrolasesAcyl indolinesCovalent inhibitionNotum inhibitorsStructural biologyWnt signalling

Identifiers

PMID36934521
PMCPMC10626578
OpenAlexW4317663883

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.